tbuckley/cabot-search huggingface dataset:
Thyroid Carcinoma, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology
Authors: Robert I Haddad, Lindsay Bischoff, Douglas Ball, Victor Bernet, Erik Blomain, Naifa Lamki Busaidy, Michael Campbell, Paxton Dickson, Quan-Yang Duh, Hormoz Ehya, Whitney S. Goldner, Theresa Guo, Megan Haymart, Shelby Holt, Jason P. Hunt, Andrei Iagaru, Fouad Kandeel, Dominick M. Lamonica, Susan Mandel, Stephanie Markovina, Bryan McIver, Christopher D. Raeburn, Rod Rezaee, John A. Ridge, Mara Y. Roth, Randall P. Scheri, Jatin P. Shah, Jennifer A. Sipos, Rebecca Sippel, Cord Sturgeon, Thomas N. Wang, Lori J. Wirth, Richard J. Wong, Michael Yeh, Carly J. Cassara, Susan Darlow
Journal: Journal of the National Comprehensive Cancer Network (2022)

Differentiated thyroid carcinomas is associated with an excellent prognosis. The treatment of choice for differentiated thyroid carcinoma is surgery, followed by radioactive iodine ablation (iodine-131) in select patients and thyroxine therapy in most patients. Surgery is also the main treatment for medullary thyroid carcinoma, and kinase inhibitors may be appropriate for select patients with recurrent or persistent disease that is not resectable. Anaplastic thyroid carcinoma is almost uniformly lethal, and iodine-131 imaging and radioactive iodine cannot be used. When systemic therapy is indicated, targeted therapy options are preferred. This article describes NCCN recommendations regarding management of medullary thyroid carcinoma and anaplastic thyroid carcinoma, and surgical management of differentiated thyroid carcinoma (papillary, follicular, Hürthle cell carcinoma).
Single-cell diploid Hi-C reveals the role of spatial aggregations in complex rearrangements and KMT2A fusions in leukemia
Authors: Zhihao Xing, Huirong Mai, Xiaorong Liu, Xiaoying Fu, Xingliang Zhang, Lichun Xie, Yunsheng Chen, Adam Shlien, Feiqiu Wen
Journal: Genome biology (2022)

Abstract Background Simple translocations and complex rearrangements are formed through illegitimate ligations of double-strand breaks of fusion partners and lead to generation of oncogenic fusion genes that affect cellular function. The contact first hypothesis states that fusion partners tend to colocalize prior to fusion in normal cells. Here we test this hypothesis at the single-cell level and explore the underlying mechanism. Results By analyzing published single-cell diploid Hi-C datasets, we find partner genes fused in leukemia exhibit smaller spatial distances than those fused in solid tumor and control gene pairs. Intriguingly, multiple partners tend to colocalize with KMT2A in the same cell. 3D genome architecture has little association with lineage decision of KMT2A fusion types in leukemia. Besides simple translocations, complex rearrangement-related KMT2A fusion genes (CRGs) also show closer proximity and belong to a genome-wide mutual proximity network. We find CRGs are co-expressed, co-localized, and enriched in the targets of the transcriptional factor RUNX1, suggesting they may be involved in RUNX1-mediated transcription factories. Knockdown of RUNX1 leads to significantly fewer contacts among CRGs. We also find CRGs are enriched in active transcriptional regions and loop anchors, and exhibit high levels of TOP2-mediated DNA breakages. Inhibition of transcription leads to reduced DNA breakages of CRGs. Conclusions Our results demonstrate KMT2A partners and CRGs may form dynamic and multipartite spatial clusters in individual cells that may be involved in RUNX1-mediated transcription factories, wherein massive DNA damages and illegitimate ligations of genes may occur, leading to complex rearrangements and KMT2A fusions in leukemia.
Intrahepatic paracrine signaling by cardiotrophin‐like cytokine factor 1 ameliorates diet‐induced NASH in mice
Authors: Tongyu Liu, Qiuyu Wang, Linkang Zhou, Peng Zhang, Lin Mi, Xiaoxue Qiu, Zhimin Chen, Henry Kuang, Siming Li, Jiandie D. Lin
Journal: Hepatology (2022)

Background and Aims: The mammalian liver harbors heterogeneous cell types that communicate via local paracrine signaling. Recent studies have delineated the transcriptomic landscape of the liver in NASH that provides insights into liver cell heterogeneity, intercellular crosstalk, and disease‐associated reprogramming. However, the nature of intrahepatic signaling and its role in NASH progression remain obscure. Approach and Results: Here, we performed transcriptomic analyses and identified cardiotrophin‐like cytokine factor 1 (CLCF1), a member of the IL‐6 family cytokines, as a cholangiocyte‐derived paracrine factor that was elevated in the liver from diet‐induced NASH mice and patients with NASH. Adenovirus‐associated virus–mediated overexpression of CLCF1 in the liver ameliorated NASH pathologies in two diet‐induced NASH models in mice, illustrating that CLCF1 induction may serve an adaptive and protective role during NASH pathogenesis. Unexpectedly, messenger RNA and protein levels of leukemia inhibitory factor receptor (LIFR), a subunit of the receptor complex for CLCF1, were markedly downregulated in NASH liver. Hepatocyte‐specific inactivation of LIFR accelerated NASH progression in mice, supporting an important role of intrahepatic cytokine signaling in maintaining tissue homeostasis under metabolic stress conditions. Conclusions: Together, this study sheds light on the molecular nature of intrahepatic paracrine signaling during NASH pathogenesis and uncovers potential targets for therapeutic intervention.
Lipid levels in midlife and risk of atrial fibrillation over 3 decades—Experience from the Swedish AMORIS cohort: A cohort study
Authors: Mozhu Ding, Alexandra Wennberg, Bruna Gigante, Göran Walldius, Niklas Hammar, Karin Modig
Journal: PLoS Medicine (2022)

Background The role of cholesterol levels in the development of atrial fibrillation (AF) is still controversial. In addition, whether and to what extent apolipoproteins are associated with the risk of AF is rarely studied. In this study, we aimed to investigate the association between blood lipid levels in midlife and subsequent risk of new-onset AF. Methods and findings This population-based study included 65,136 individuals aged 45 to 60 years without overt cardiovascular diseases (CVDs) from the Swedish Apolipoprotein-Related Mortality Risk (AMORIS) cohort. Lipids were measured in 1985 to 1996, and individuals were followed until December 31, 2019 for incident AF (i.e., study outcome). Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox regression, adjusting for age, sex, and socioeconomic status. Over a mean follow-up of 24.2 years (standard deviation 7.5, range 0.2 to 35.9), 13,871 (21.3%) incident AF cases occurred. Higher levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were statistically significantly associated with a lower risk of AF during the first 5 years of follow-up (HR = 0.61, 95% CI: 0.41 to 0.99, p = 0.013; HR = 0.64, 95% CI: 0.45 to 0.92, p = 0.016), but not thereafter (HR ranging from 0.94 [95% CI: 0.89 to 1.00, p = 0.038] to 0.96 [95% CI: 0.77 to 1.19, p &gt; 0.05]). Lower levels of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (ApoA-I) and higher triglycerides (TG)/HDL-C ratio were statistically significantly associated with a higher risk of AF during the entire follow-up (HR ranging from 1.13 [95% CI: 1.07 to 1.19, p &lt; 0.001] to 1.53 [95% CI: 1.12 to 2.00, p = 0.007]). Apolipoprotein B (ApoB)/ApoA-I ratio was not associated with AF risk. The observed associations were similar among those who developed incident heart failure (HF)/coronary heart disease (CHD) and those who did not. The main limitations of this study include lack of adjustments for lifestyle factors and high blood pressure leading to potential residual confounding. Conclusions High TC and LDL-C in midlife was associated with a lower risk of AF, but this association was present only within 5 years from lipid measurement and not thereafter. On the contrary, low HDL-C and ApoA-I and high TG/HDL-C ratio were associated with an increased risk of AF over almost 35 years of follow-up. ApoB/ApoA-I ratio was not associated with AF risk.
Six-Year Results From RELEVANCE: Lenalidomide Plus Rituximab (R<sup>2</sup>) Versus Rituximab-Chemotherapy Followed by Rituximab Maintenance in Untreated Advanced Follicular Lymphoma
Authors: Franck Morschhauser, Loretta Nastoupil, Pierre Feugier, Jean-Marc Schiano de Colella, Hervé Tilly, Maria Lia Palomba, Emmanuel Bachy, Christophe Fruchart, Edward N. Libby, Rene-Olivier Casasnovas, Ian W. Flinn, Corinne Haioun, Hervé Maisonneuve, Loic Ysebaert, Nancy L. Bartlett, Kamal Bouabdallah, Pauline Brice, Vincent Ribrag, Steven Le Gouill, Nicolas Daguindau, Stéphanie Guidez, Gian Matteo Pica, Alejandro Martín García-Sancho, Armondo López-Guillermo, Jean-François Larouche, Kiyoshi Ando, Maria Gomes da Silva, Marc André, Wu Kalung, Laurie H. Sehn, Koji Izutsu, Guillaume Cartron, Argyrios Gkasiamis, Russell Crowe, Luc Xerri, Nathan H. Fowler, Gilles Salles
Journal: Journal of Clinical Oncology (2022)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The RELEVANCE trial (ClinicalTrials.gov identifier: NCT01650701) showed that lenalidomide plus rituximab (R2) provided similar efficacy to rituximab plus chemotherapy (R-chemo) in patients with advanced-stage, previously untreated follicular lymphoma (FL). We report the second interim analysis of the RELEVANCE trial after 6 years of follow-up. Patients with previously untreated grade 1-3a FL were assigned 1:1 to R2 or R-chemo, followed by rituximab maintenance. Coprimary end points were complete response (confirmed/unconfirmed) at week 120 and progression-free survival (PFS). At median follow-up of 72 months, 6-year PFS was 60% and 59% for R2 and R-chemo, respectively (hazard ratio = 1.03 [95% CI, 0.84 to 1.27]). Six-year overall survival was estimated to be 89% in both groups. Median PFS and overall survival were not reached in either group. Overall response after progression was 61% and 59%, and 5-year estimated survival rate after progression was 69% and 74% in the R2 and R-chemo groups, respectively. The transformation rate per year in the R2 and R-chemo groups was 0.68% and 0.45%, and secondary primary malignancies occurred in 11% and 13% (P = .34), respectively. No new safety signals were observed. R2 continues to demonstrate comparable, durable efficacy and safety versus R-chemo in previously untreated patients with FL and provides an acceptable chemo-free alternative.
The Critical Role of Academic Clinical Trials in Pediatric Cancer Drug Approvals: Design, Conduct, and Fit for Purpose Data for Positive Regulatory Decisions
Authors: Bram De Wilde, Elly Barry, Elizabeth Fox, Dominik Karres, Mark Kieran, John Manlay, Donna Ludwinski, Gregory Reaman, Pamela Kearns
Journal: Journal of Clinical Oncology (2022)

PURPOSE For decades, academic clinical trials consortia have collaborated to optimize outcomes for childhood cancers through evaluating incremental improvements in conventional mutimodality treatment regimes. There are now increasing opportunities to partner with industry to test new medicines in academic-sponsored trials, but these collaborative studies rarely contribute to marketing authorizations. We addressed why this is the case and sought solutions to enable academic-sponsored trials to directly contribute to the licensing of new medicines. METHODS Under the auspices of the multistakeholder platform ACCELERATE, we convened a working group of representatives from clinical academia, pharmaceutical industry, European Medicines Agency, US Food and Drug Administration, and patient advocacy to define the challenges and propose recommendations to facilitate academic-sponsored trial design and conduct to be aligned to both the needs of the pharmaceutical company who own the asset and the expectations of the regulatory (licensing) authorities. RESULTS We identified that although academic consortia have long-standing expertise to conduct robust clinical trials, there were critical gaps in knowledge, standard procedures, and resources that hindered the trial data directly contributing to marketing authorization applications. We propose a suite of recommendations focused on (1) essential documents, (2) essential data, (3) data management, and (4) trial resources, specifically aimed at enabling academic-industry partnerships to deliver an academic-sponsored trial that meets the requirements for a marketing authorization submission. These recommendations pivot around transparency in academic-industry partnerships and early engagement with regulators. CONCLUSION Academic sponsors and industry partners need to prospectively recognize when the planned collaborative trial could contribute to an application to marketing authorization and plan accordingly. Transparent collaboration and knowledge sharing between the partners opens an important pathway for accelerating new treatments into clinical practice for children with cancer.
Geographic Accessibility and Availability of Radiotherapy in Ghana
Authors: Aba Anoa Scott, Alfredo Polo, Eduardo Zubizarreta, Charles Akoto-Aidoo, Clement Edusa, Ernest Osei-Bonsu, Joel Yarney, Bismark Dwobeng, Michael Milosevic, Danielle Rodin
Journal: JAMA Network Open (2022)

Importance Radiotherapy is critical for comprehensive cancer care, but there are large gaps in access. Within Ghana, data on radiotherapy availability and on the relationship between distance and access are unknown. Objectives To estimate the gaps in radiotherapy machine availability in Ghana and to describe the association between distance and access to care. Design, Setting, and Participants This is a cross-sectional, population-based study of radiotherapy delivery in Ghana in 2020 and model-based analysis of radiotherapy demand and the radiotherapy utilization rate (RUR) using the Global Task Force on Radiotherapy for Cancer Control investment framework. Exposures Receipt of radiotherapy and the number of radiotherapy courses delivered. Main Outcomes and Measures Geocoded location of patients receiving external beam radiotherapy (EBRT); median Euclidean distance from the district centroids to the nearest radiotherapy centers; proportion of population living within geographic buffer zones of 100, 150, and 200 km; additional capacity required for optimal utilization; and geographic accessibility after strategic location of a radiotherapy facility in an underserviced region. Results A total of 2883 patients underwent EBRT courses in 2020, with an actual RUR of 11%. Based on an optimal RUR of 48%, 11 524 patients had an indication for radiotherapy, indicating that only 23% of patients received treatment. An investment of 23 additional EBRT machines would be required to meet demand. The median Euclidean distance from the district centroids to the nearest radiotherapy facility was 110.6 km (range, 0.62-513.2 km). The proportion of the total population living within a radius of 100, 150 and 200 km of a radiotherapy facility was 47%, 61% and 70%, respectively. A new radiotherapy facility in the northern regional capital would reduce the median of Euclidean distance by 10% to 99.4 km (range, 0.62-267.7 km) and increase proportion of the total population living within a radius of 100, 150 and 200 km to 53%, 69% and 84%, respectively. The greatest benefit was seen in regions in the northern half of Ghana. Conclusions and Relevance In this cross-sectional study of geographic accessibility and availability of radiotherapy, Ghana had major national deficits of radiotherapy capacity, with significant geographic disparities among regions. Well-planned infrastructure scale-up that accounts for the population distribution could improve radiotherapy accessibility.
Preemptive Removal of Small, Asymptomatic Kidney Stones
Authors: David S Goldfarb
Journal: New England Journal of Medicine (2022)

Asymptomatic kidney stones are often noted on imaging studies that are performed to screen for stones or when a patient presents with symptomatic stones. Patients frequently ask two questions about the asymptomatic stones: “Will my stones ever become symptomatic?” and “How do we get those stones to come out before they get bigger?” These excellent queries derive from the patient’s knowledge that smaller stones can pass spontaneously but that the misery entailed by renal colic is memorable.1 The answer to the first query is “Yes, those stones are likely to become symptomatic.” But data are lacking on methods for getting . . .
Short-term outcomes of robotic versus open pancreaticoduodenectomy in elderly patients: A multicenter retrospective cohort study
Authors: Qu Liu, Nan Jiang, Eryun Tian, Mengyang Li, Huating Zhang, Guodong Zhao, Xiaodong Tan, Wei Wang, Bing Han, Jianlei Yuan, Qin Gan, Yuntao Ma, Zhiming Zhao, Rong Liu
Journal: International Journal of Surgery (2022)
The Implications of the Supreme Court Decision to Overturn <i>Roe v Wade</i> for Women With Pregnancy-Associated Cancers
Authors: Jordyn Silverstein, Katherine Van Loon
Journal: JAMA Oncology (2022)

This Viewpoint evaluates factors introduced by the overturn of Roe v Wade that will further complicate the complex, multidisciplinary decision-making involved in treating patients with pregnancy-associated cancer.
T-Cell Engagers — Modern Immune-Based Therapies for Multiple Myeloma
Authors: Sham Mailankody, Ola Landgren
Journal: New England Journal of Medicine (2022)

B-cell maturation antigen (BCMA) was identified as a prognostic marker in multiple myeloma more than two decades ago. Starting in 2014, the first use of BCMA as a treatment target was evaluated in patients with multiple myeloma who received chimeric antigen receptor (CAR) T cells.1,2 Today, a range of myeloma treatments target BCMA, including CAR T cells, along with antibody drug conjugates and bispecific antibodies; some agents are in development, and some have been approved by the Food and Drug Administration (FDA).3 The rapid translation from preclinical studies to several FDA-approved treatments is a new chapter in the remarkable success . . .
Improving interferon-γ release assay interpretation: are IP-10 and MIG the solution?
Authors: Francesca Saluzzo, Claudia M. Denkinger, Daniela M. Cirillo
Journal: European Respiratory Journal (2022)

<b>As a gold standard to diagnose TB infection remains elusive, the need to identify new biomarkers to support the tools we currently rely on endures. IP-10 and MIG detection could improve IGRA interpretation.</b> https://bit.ly/3wUGD0Z
Analysis of Epinephrine Dose, Targeted Temperature Management, and Neurologic and Survival Outcomes Among Adults With Out-of-Hospital Cardiac Arrest
Authors: Betty Y. Yang, Natalie Bulger, Richard Chocron, Catherine R. Counts, Chris Drucker, Lihua Yin, Megin Parayil, Nicholas J. Johnson, Nona Sotoodehenia, Peter J. Kudenchuk, Michael R. Sayre, Thomas D. Rea
Journal: JAMA Network Open (2022)

Epinephrine improves return of spontaneous circulation after out-of-hospital cardiac arrest (OHCA). These beneficial cardiac effects do not directly translate to better neurologic outcomes, possibly because of epinephrine-induced microvascular effects that produce critical brain ischemia.To examine whether targeted temperature management (TTM) modifies the adverse association between increasing prehospital epinephrine dose and neurologically favorable survival.This retrospective cohort study assessed 14 612 adults from Seattle and King County, Washington, with nontraumatic OHCA between January 1, 2008, and December 31, 2018, and included those who achieved return of spontaneous circulation and were unconscious at hospital admission. Data analysis was performed from April 2021 to May 2022.Epinephrine dose and TTM during prehospital resuscitation.Favorable neurologic survival (Cerebral Performance Category [CPC] 1 or 2) and survival to hospital discharge.Of the 14 612 assessed adults, 5253 (median age, 63 years; IQR, 51-74 years; 3460 [65.8%] male) were eligible for the study. The median epinephrine dose was 2.0 mg (IQR, 1.0-3.0 mg); 3052 patients (58.1%) received TTM. In all, 1889 patients (36.0%) survived with CPC 1 to 2, and 2177 (41.4%) survived to discharge. Increasing doses of epinephrine were associated with a decreasing likelihood of CPC 1 to 2 (odds ratio [OR], 0.46; 95% CI 0.42-0.50 for each additional milligram of epinephrine) and survival (OR, 0.47; 95% CI, 0.43-0.51). The dose-dependent epinephrine association was modified by TTM. After adjusting for Utstein covariates, TTM was associated with a relative stepwise improvement in odds of CPC 1 to 2 (interaction OR, 1.36; 95% CI, 1.22-1.51) and survival (interaction OR, 1.37; 95% CI, 1.24-1.51). A significant interaction was also observed when the analysis was stratified according to initial rhythm among shockable OHCA and nonshockable OHCA (shockable interaction OR, 1.20; 95% CI, 1.04-1.39; and nonshockable interaction OR, 1.24, 95% CI, 1.07-1.45).This cohort study found an interaction between TTM and epinephrine dose such that the beneficial association of TTM increased with increasing epinephrine dose, suggesting that TTM may attenuate the adverse effects of higher-dose epinephrine.
Correction: Neurotensin promotes the progression of malignant glioma through NTSR1 and impacts the prognosis of glioma patients
Authors: Qing Ouyang, Xueyang Gong, Hualiang Xiao, Ji Zhou, Minhui Xu, Yun Dai, Lunshan Xu, Hua Feng, Hongjuan Cui, Liang Yi
Journal: Molecular Cancer (2022)

cells by mistake.The corrected Figure 4 is now shown in this correction.
The recombination landscape of the Khoe-San likely represents the upper limits of recombination divergence in humans
Authors: Gerald van Eeden, Caitlin Uren, Evlyn Pless, Mira Mastoras, Gian D. van der Spuy, Gerard Tromp, Brenna M. Henn, Marlo Möller
Journal: Genome biology (2022)

Abstract Background Recombination maps are important resources for epidemiological and evolutionary analyses; however, there are currently no recombination maps representing any African population outside of those with West African ancestry. We infer the demographic history for the Nama, an indigenous Khoe-San population of southern Africa, and derive a novel, population-specific recombination map from the whole genome sequencing of 54 Nama individuals. We hypothesise that there are no publicly available recombination maps representative of the Nama, considering the deep population divergence and subsequent isolation of the Khoe-San from other African groups. Results We show that the recombination landscape of the Nama does not cluster with any continental groups with publicly available representative recombination maps. Finally, we use selection scans as an example of how fine-scale differences between the Nama recombination map and the combined Phase II HapMap recombination map can impact the outcome of selection scans. Conclusions Fine-scale differences in recombination can meaningfully alter the results of a selection scan. The recombination map we infer likely represents an upper bound on the extent of divergence we expect to see for a recombination map in humans and would be of interest to any researcher that wants to test the sensitivity of population genetic or GWAS analysis to recombination map input.